96. Jahrestagung der Deutschen Gesellschaft für Pathologie e. V ...

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to assess the correct rate of R1 resected patients and also the correlation between R1 resections and clinical outcome. The optimal standardized protocol for Whipple specimens, involving multicolor margin staining, axial slicing and extensive tissue sampling, has to be applied. The R classification is defined for any given tumor as R0, no residual tumor; R1, microscopic residual tumor; R2, macroscopic residual tumor. Since these definitions are internationally accepted, the concept of „circumferential resection margins“ is introduced for pancreatic cancer, describing the relation of the tumor edge to the circumferential margin (CRM). The pathologist has to measure the exact distance of the tumor to the definite resection margin. Tumors with a minimal distance from the CRM of < or=1 mm are categorized as CRM-positive, tumor with a distance of >1 mm are CRM-negative – in both cases a curative resection occurred. Only in the case of tumor cells visible directly at the resection margin, a R1 resection is diagnosed. The different use of both definitions of resection margin involvement improves valid comparisons between reports on treatment results. The CRM concept of pancreatic carcinoma will be introduced in the revised version of the S3 guideline. VO-031 Molecular pathology of pancreatic adenocarcinoma P . Michl1 1Klinik für Gastroenterologie, Endokrinologie und Stoffwechsel, Philipps- Universität, Marburg Pancreatic cancer carries the most dismal prognosis of all solid tumors and is associated with a 5-year survival rate of less than 5%. Identification of novel, urgently required therapeutic modalities depends on detailed knowledge of the underlying molecular pathology. During recent years, progress has been made in deciphering the complex network of signaling cascades involved in cancerogenesis and tumor progression in pancreatic cancer. Furthermore, genetically engineered mouse models have been developed, including a model with conditionally activating mutation of K-Ras and inactivating mutation of p53, both of which are frequently found in the human disease. The murine tumors closely recapitulate histological and clinical presentation of human pancreatic tumor development and progression and are suitable for studying the impact of genetic manipulation of specific genes as well as for testing novel pharmacological inhibitors. In addition, accumulating evidence suggests a dominant role for the desmoplastic stromal reaction that comprises up to 90% of the tumor volume in mediating tumor progression. Signaling events within the tumor stroma such as activation of the hedgehog pathway have been shown to influence tumor growth, angiogenesis and resistance to chemotherapy. Moreover, infiltrating inflammatory cells within the stromal compartment have been shown to contribute to the resistant phenotype of this tumor entity. Numerous preclinical and clinical trials targeting tumor cell autonomous and non-autonomous stromal signaling cascades are currently underway to overcome the resistance to chemotherapy and to improve the appalling prognosis of pancreatic cancer. Keynote Lecture VO-032 The epithelial-mesenchymal transition and cancer stem cells R .A . Weinberg1 1Whitehead Institute, Massachusetts Institute of Technology, Cambridge, United States The molecular and the cellular mechanism of tumor progression have been elusive until recently. In particular, the mechanisms of invasion and metastasis have proven difficult to elucidate. These last steps of malignant progression involve a succession of steps often termed the “invasion-metastasis cascade”, which includes local invasion by primary tumor cells, intravasation, passage through the systemic circulation, extravasation, formation of micrometastatic colonies, and the outgrowth of the latter in macroscopic growths, often termed colonization. In recent years, a cell-biological program termed the epithelial-mesenchymal transition (EMT) has been studied in great depth because it holds the promise of explaining many of the steps of this complex cascade. Thus, by passing through this program, a carcinoma cell acquires the attributes required to complete most of the steps of the invasion-metastasis cascade, quite possibly all of them except for the last step, colonization. This represents an enormous simplification of our conceptualization of this process, as it may represent nothing more than the activation of an otherwise-latent cell-biological program that is normally operative during embryogenesis and, in adults, wound-healing. Over the past several years, an additional aspect of the EMT program has come to light, as it has been found to be intertwined with the epithelial stem cell program. Thus, cells that have passed through the EMT program approach the stem-cell state. This holds important implications for both normal epithelial and neoplastic epithelial cells, as they both exploit the same program to organize themselves. In the context of metastasis, this implies that a cell that has pass through an EMT also acquires the self-renewal capability needed to seed a new colony of metastatic cells, an important prerequisite to successful colonization Mechanisms of Progression and Therapy Resistance of Cancer I – English VO-033 Programmed necrosis W . Roth1 1Institute of Pathology, University Hospital Heidelberg, and German Cancer Research Center, Heidelberg The research on cell death regulation has become one of the most important areas in tumor biology. Due to the central role of cell death regulation in tumor development and therapy resistance, a detailed knowledge of the molecular mechanisms of cell death opens up the possibility to develop novel rational therapeutic approaches for cancer. During the last decades the research on cell death was dominated by an oversimplified dual concept of apoptosis versus necrosis: Apoptosis was defined as an active, molecularly determined signaling cascade leading to “programmed cell death”, whereas necrosis was conceived as a passive process resulting from unspecific cellular damage. However, in the last few years this dogmatic conception has dramatically changed. Several studies clearly demonstrate that certain forms of necrotic cell death are executed in a strictly regulated and ordered fashion. The best known type of programmed necrosis is “necroptosis” which describes a signaling cascade mediated by TNF receptor 1 and RIP1 leading to cell death. Necroptosis plays an important role in the embryonic development, but also in the pathophysiology of certain diseases such as chronic inflammatory bowel disease. Yet another necrosis-like type of cell death can be induced by the HMGB1 protein. The HMGB1-induced cell death is morphologically characterized by the formation of giant mitochondria and metabolically by a severe deregulation of mitochondrial oxidative phosphorylation. The elucidation of the molecular mechanisms of necrotic cell death is an important step to develop novel strategies to overcome the classical resistance to apoptotic cell death which is one of the main reasons for therapy resistance in many types of cancer. Der Pathologe · Supplement 1 · 2012 | 13
Abstracts VO-034 Interplay of cadherins in breast cancer progression M . Rezaei 1 , K . Friedrich 1 , A . Kettelhake 1 , B . Wielockx 1 , G . Baretton 1 , G . Breier 1 1 University Hospital Carl Gustav Carus, TU Dresden, Institute of Pathology, Dresden Introduction. Deregulation of cadherin expression, such as the loss of epithelial (E-)cadherin and gain of neural (N-)cadherin, has been implicated in carcinoma progression. We have previously shown that vascular endothelial (VE-)cadherin can be expressed on human breast cancer cells, in addition to tumor endothelial cells. This aberrant expression pattern was recapitulated in a mouse mammary carcinoma model, and functional studies showed that VE-cadherin promotes experimental tumor growth by stimulating transforming growth factor (TGF)-beta signaling in cancer cells. Here, we have investigated the functional interplay between N-cadherin and VE-cadherin in breast cancer. Methods. The expression of N-cadherin and VE-cadherin was evaluated by immunohistochemistry in a tissue micro-array with 84 invasive human breast carcinomas. VE-cadherin and N-cadherin expression in mouse breast cancer cells was manipulated by RNA-interference or overexpression and analysed by immunofluorescence, reverse transcriptasepolymerase chain reaction, and western blot. Experimental tumors were generated by transplantation of the modified mouse breast cancer cells into immunocompetent mice. Tumor growth was monitored, and tumor tissue was subjected to histological analysis. Results. VE-cadherin and N-cadherin were largely co-expressed in invasive human breast cancers. Silencing of N-cadherin in mouse mammary carcinoma cells led to decreased VE-cadherin expression and induced changes indicative of mesenchymal-epithelial reverting transition (MET), as indicated by re-induction of E-cadherin, localisation of β-catenin at the cell membrane, decreased expression of vimentin and SIP1, and gain of epithelial morphology. Suppression of N-cadherin expression in mammary carcinoma cells inhibited tumor growth in vivo even with forced expression of VE-cadherin. Conclusions. The results underline the critical role of N-cadherin in breast cancer progression and show that N-cadherin is involved in the maintenance of the malignant fibroblastoid tumor cell phenotype. Ncadherin prevents the re-expression of E-cadherin and the localisation of β-catenin at the plasma membrane; consequently, β-catenin can exert its known protumorigenic activity in the cell nucleus. N-cadherin is also required to maintain the expression and protumorigenic activity of VEcadherin in malignant tumor cells but not vice versa. Thus, N-cadherin acts in concert with VE-cadherin to promote tumor growth. VO-035 Cancer stem cells: targets and potential biomarkers for radiotherapy M . Krause1 1Dept . of Radiation Oncology, OncoRay Center for Radiation Research in Oncology Radiotherapy has a curative potential in solid human tumours. Even in locally advanced, inoperable tumours, many patients can still be cured by radiotherapy or radiochemotherapy, e.g. up to 40% in advanced head and neck cancer. The current understanding of cancer stem cells (CSC) defines a CSC as a tumour cell that has the unique potential to self-renew and to regenerate a complete tumour with all its sublines of tumour cells. This definition implies that all CSC need to be inactivated to reach a permanent local tumour control, or, that a single surviving CSC after treatment will cause a recurrence. Thus, CSC should be ideal biomarkers and targets for radiotherapy. Today, there some evidence for a higher radioresistance of CSC measured by surface markers that are higher expressed in CSC versus non- CSC. If such biological differences hold true, CSC need to be included 14 | Der Pathologe · Supplement 1 · 2012 into the development of new predictive biomarkers. Recently, for the first time a systematic clinical study has shown a predictive value for the expression of the surface marker CD44 for local tumour control after primary radiotherapy of early laryngeal cancer. However, it has to be expected that in other tumour entities, the heterogeneity will be larger due to confounding factors of radiation resistance, e.g. tumour size or tumour micromilieu. The talk will give an overview on the current knowledge of the potential value of CSC for prediction of tumour control after radiotherapy. First attempts of specific targeting approaches will be discussed. Mechanisms of Progression and Therapy Resistance of Cancer II – English VO-036 The role of HIF-prolyl hydroxylase-2 (PHD2) during physiological and pathological processes in mice B . Wielockx 1 1TUDresden – Pathology, Dresden Hypoxia is a prominent feature during development and physiological as well as pathological conditions in adults. An oxygen-sensing machinery is therefore very important to help the cells adapt instantaneously to any unacceptable O2 level. Such a system relies on the oxygen dependent HIF-prolyl hydroxylases (PHD1–3), enzymes that can inactivate the alpha subunit of the hypoxia inducible transcription factor (HIF). HIF1α is ubiquitously expressed in all tissues, whereas HIF2α is restricted to certain cell types. In case of low oxygen availability, PHDs lose their functionality and allow the HIF complex, composed of HIFα and a constitutive HIFβ subunit, to promote biochemical and physiological changes including anaerobic glycolysis, angiogenesis and hematopoiesis. We produced a mouse line that lacks HIF prolyl hydroxylase2 (PHD2) in different cell types (e.g. hematopoietic cells, epithelial cells). Moreover, these conditional PHD2-deficient mice display strongly elevated hematocrit levels (up to 85%) together with high EPO concentrations in the blood produced by kidney and brain. Remarkably, these mice show no premature lethality. In addition, we observed an enlargement of the spleen which we showed to be the major organ responsible for the enormous overproduction of RBCs. Double cKO mice revealed that the erythrocytosis phenotype is exclusively driven by HIF2 α whereas HIF1 α is responsible for the survival of cKO mice. Next, we found that the hematopoietic stem cell (HSC) compartment in the bone marrow was significantly altered. Detailed FACS analyses demonstrated that cKO mice contain much more proliferating multipotent progenitors (MPPs) under steady state conditions; an effect induced by HIF1 α . On the other hand, severe stress situations pushed quiescent cKO CD34neg HSCs to self-renewal. In addition, we subjected these cKO mice to different in vivo models highlighting the central role of PHD2 during inflammatory related disorders. VO-037 Role of autophagy in cancer K . Datta1 1Department of Biochemistry, University of Nebraska Medical Center, Nebraska, United States Autophagy is a regulated catabolic pathway that promotes lysosomal degradation of damaged proteins, cellular organelles, and other macromolecules. This self-digestion process, which facilitates the recycling of bioenergetic components, is activated by a number of stimuli, including the presence of reactive oxygen species, deprivation of growth factors,
Page 2 and 3: Inhalt Der Pathologe · Supplement
Page 4 and 5: Inhalt Der Pathologe · Supplement
Page 6 and 7: Editorial Liebe Kolleginnen und Kol
Page 8 and 9: Kolorektales Karzinom 2 VO-005 Tran
Page 10 and 11: Keynote Lecture VO-014 Genetic dete
Page 12 and 13: (AMACR, FASN, GOLM1, GSP-pi, ERG) t
Page 16 and 17: DNA damage, and cytotoxic drugs. Au
Page 18 and 19: HCV-positive formalin-fixed and par
Page 20 and 21: well as MET activation were examine
Page 22 and 23: or BRAF mutation, c-MYC and SIRT1 e
Page 24 and 25: AG Pneumopathologie III DO-032 Remo
Page 26 and 27: immature granulopoiesis showed a st
Page 28 and 29: ned, if well-defined mantle zones,
Page 30 and 31: phomas). Most prominent gains or am
Page 32 and 33: DO-062 Tumor-associated macrophages
Page 34 and 35: DO-080 DOG1: an immunohistochemical
Page 36 and 37: AG Oralpathologie DO-087 Detection
Page 38 and 39: DO-094 Do activated fibroblasts inf
Page 40 and 41: DO-101 Histopathological analysis o
Page 42 and 43: DO-108 Identification of potential
Page 44 and 45: Conclusions. In conclusion, 454 par
Page 46 and 47: subgroup of patients with B-Raf mut
Page 48 and 49: DO-002b Impact of terminologies in
Page 50 and 51: Methods. We performed MCPyV-FISH of
Page 52 and 53: FR-013 HPV-genotype distribution in
Page 54 and 55: Methods. Three different techniques
Page 56 and 57: (i.e. investment in equipment and e
Page 58 and 59: FR-032 COLD-PCR: a powerful tool in
Page 60 and 61: dissection (MBLND) technique to imp
Page 62 and 63: SO-005 Prevalence of mutations in s
Page 64 and 65:
SO-011 Methylation profiling and in
Page 66 and 67:
more effective than SAHA alone and
Page 68 and 69:
SO-022 Specialized pathology review
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SO-027 Ki-67 in mitotic score group
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nificantly associated with advanced
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liver did not correlate with the mu
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AG Paidopathologie II SO-046 Overex
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Results. Histomorphology of the ova
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p42 and p27 have not yet been inves
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SO-068 Recent advances in understan
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SO-075 A novel, dual role of CCN3 i
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Pancreatic Adenocarcinoma SG-137 Se
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sease and 30 colon cancer serum sam
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Conclusions. Although CRC is charac
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differentiated and TNM stage III or
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pressed moderate levels of the prot
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FR-P-037 MALDI imaging reveals COX7
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in the context of therapy response
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on primary cells of wild-type and c
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chemotherapy was recommended and co
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aims are twofold: 1) to verify the
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Results. Her2/neu status in TMAs an
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prognostic impact was found in rect
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provided information on survival ti
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Methods. Biopsy specimens from 430
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the OS rate was 53% for patients wi
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FR-P-098 Immunohistological stainin
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FR-P-104 Histopathological evaluati
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within the earliest morphologic det
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Conclusions. In primary imaging a g
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fibrotic neointma development as we
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FR-P-129 Alpha-1-antitrypsin-PiZ-an
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FR-P-136 The expression of central
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cosa and in the periarterial tissue
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FR-P-149 Combination of Castleman d
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or without different concentrations
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Results. In 18 cases (79%) the caus
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FR-P-168 Autopsy findings in a 2-ye
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FR-P-174 MPGN-like glomerulonephrit
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Poster: Gynäkopathologie und Mamma
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SA-P-011 Genetic aberrations of pre
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Mechanismen, die eine Progression d
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internet server. A network of inter
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Methods. HE-gefärbte Schnittpräpa
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Conclusions. The newly released 450
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and desmoplastic reaction are diffe
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one patient revealed more than 9 mi
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situation, the V600E mutation in th
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SA-P-064 Evolution of molecular pat
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nic markers such as myf4 and MyoD1
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Conclusions. To our knowledge, this
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SA-P-085 Expression of the eukaryot
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Results. The papillary RCC type II
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SA-P-098 Male infertility: assessme
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SA-P-104 Process oriented scientifi
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Conclusions. The IBDW offers a uniq
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L Lasitschka F. DO-046 Lehmann A. F
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96. Jahrestagung der Deutschen Gesellschaft für Pathologie e. V ...

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